February 28, 2012

Vertex Pharmaceuticals' (NAS: VRTX) Incivek isn't even in the coffin yet, but its obituary has been written by me and others. Sales have peaked -- or will soon -- as hepatitis C patients wait for new medications that don't have to be administered with Roche's Pegasys or Merck's (NYS: MRK) Pegintron, injectable drugs with unpleasant side effects.

Vertex is hoping that one of those all-oral drug combinations will still include Incivek, even if it has to develop the cocktail itself. Last week the company announced phase 2 data for a combination of Incivek, ribavirin -- an oral medication currently taken with Incivek and Pegasys/Pegintron -- and a new medication, VX-222.

A respectable 83% of patients had undetectable virus levels after taking the three-drug combination for 12 weeks. Some of those patients are going to rebound -- two of 11 patients who reached four weeks post-treatment have relapsed -- but the data is solid enough to justify moving into a larger phase 2b trial, which will help guide the design of a phase 3 trial. If that's positive, Vertex hopes for approval by early 2015.

The worry here is that Vertex might be throwing good money into useless clinical trials if Incivek becomes obsolete. The blockbuster is a protease inhibitor, but there are plenty of next-generation protease inhibitors in development: Bristol-Myers Squibb's (NYS: BMY) asunaprevir, Johnson & Johnson's (NYS: JNJ) TMC435, Achillion Pharmaceuticals' (NAS: ACHN) ACH-1625, and others. None is on the market -- they'll all have to prove themselves in the clinic -- but considering how many there are, it seems likely that one will be able to beat Incivek on the efficacy or safety front.

Going forward, though, drugs' efficacies won't be measured individually, but as part of a cocktail. For an all-Vertex cocktail to work, the company needs VX-222 and other drugs in its pipeline to make up for any shortcomings Incivek might have versus other protease inhibitors in other cocktails.

It could happen, for sure -- I wouldn't count Vertex out just yet -- but the company might be better off ditching Incivek and partnering up with others to help get its pipeline drugs into whatever standard-of-care cocktail is eventually developed.

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The technique allows doctors to monitor how well the organ functions and means livers can be stored for far longer.

February 27 2012 at 10:22am By JO MACFARLANE

London - Scientists have created a machine which can keep donor livers functioning outside the body.

The breakthrough - a British first - could save the lives of hundreds of people needing liver transplants every year.

Livers taken from organ donors are currently packed in ice for up to 12 hours to prevent them from decay while they are transported, but this technique can affect the blood vessels and cause excess fat on the organ to solidify.

It means many are considered unsuitable for use and are discarded, despite the wishes of patients and families. In other cases the livers fail because of the damage caused to them during the transplant process.

The new machine keeps the liver in a solution at body temperature and feeds it with blood, oxygen and nutrients.

The technique allows doctors to monitor how well the organ functions and means livers can be stored for far longer - up to 24 hours - before being transplanted.

Known as METRA, the machine was originally used on pig livers but a recent trial found that out of 13 human livers discarded by doctors, six would have been good enough to be transplanted.

The machine was developed by Organox, a company linked to Oxford University which was set up by Professor Peter Friend, director of the Oxford Transplant Centre. He said: “The results show the machine can keep a donor liver healthy as if it is still in the human body. You also can see if it is functioning well enough for transplant.

“Decisions on usability are made purely on visual judgment. That is all surgeons have at the moment. That is why this machine is so useful.”

Surgeon David Mayer, liver lead for NHS Blood and Transplant, described the research as “extremely exciting”.

He said: “If this machine comes into use then it will almost certainly increase the number of livers we can transplant.”

Further trials involving patients are set to be approved later this year. - Mail on Sunday

San Francisco—A second Phase IIb study of a new oral therapy for hepatitis C, PSI-7977, taken once daily, increased sustained virologic response (SVR) rates up to 91% in patients with difficult-to-treat hepatitis C virus (HCV) genotype 1 infection—a substantial improvement from the 50% reported in patients who received standard peginterferon and ribavirin (Peg-IFN/RBV) therapy. The study also showed significant advantages of PSI-7977 in patients who typically have poor responses to interferon.

Investigators say the new drug has the potential to dramatically alter the treatment paradigm for patients with hepatitis C virus (HCV) infection. “That’s true for all genotypes and all patients,” said lead author Eric J. Lawitz, MD, medical director of Alamo Medical Research, in San Antonio.

Patients who have the interleukin-28B (IL28B) TT genotype generally have a much lower chance of responding to IFN than people with the CC or CT genotypes. Yet in this study, these patients achieved high SVR rates to PSI-7977. Of the 13 patients who carried the TT allele, all tested negative for HCV by the third week of treatment and achieved SVR at week 12.

“The high SVR of greater than 90% in HCV genotype 1 patients was independent of predictors of poor IFN response,” Dr. Lawitz said.

Results from the two studies sparked considerable excitement among attendees of The Liver Meeting about this investigational therapy.

“I think it’s proof of principle that the proper combination of direct-acting antivirals can, in fact, produce enough suppression of viral replication to result in extinction of infection without the benefit of a broadly acting antiviral like IFN,” said Raymond Chung, MD, chief of hepatology and vice-chief of gastroenterology at Massachusetts General Hospital, in Boston.

The PROTON study was designed to examine dose-dependent response rates for PSI-7977 in HCV genotype 1–infected patients. Investigators enrolled 121 treatment-naive patients with this genotype in a randomized, double-blind, placebo-controlled, dose-ranging fashion. All patients were at least 18 years old with an HCV RNA level of 50,000 IU/mL or greater, platelets greater than 90,000/mm3, neutrophils greater than 1,500/mm3, and a hemoglobin level of at least 11 g/dL, with no evidence of cirrhosis.

Trial participants were randomized in a 2:2:1 ratio to one of three treatment arms: PSI-7977 200 or 400 mg daily in combination with IFN and RBV (n=48 and n=47, respectively) or Peg-IFN/RBV alone (n=26). Patients in the PSI-7977 arms received triple therapy for 12 weeks, followed by an additional 12 weeks of Peg-IFN/RBV. All patients who achieved early rapid virologic response (RVR) discontinued therapy at 24 weeks, while all others continued therapy for a total of 48 weeks. Patients in the IFN and RBV arm received treatment for 48 weeks.

Analysis showed robust response rates among all PSI-7977 patients regardless of dose. Patients who received 200 mg daily showed an RVR rate of 98%, an early RVR rate of 98% and an end-of-treatment response rate of 91%. Patients receiving 400 mg showed a 98% RVR, 91% early RVR and 91% end-of treatment response through 24 weeks. In contrast, response rates among patients who received Peg-IFN/RBV alone were 19%, 50% and 50%, respectively.

In an as-treated analysis of patients who received at least eight weeks of PSI-7977, 88% of those in the 200-mg arm and 98% of those in the 400-mg arm achieved an SVR at 12 weeks.

Several failures occurred in the trial. Three patients in the 200-mg arm who had viral suppression during the first 12 weeks of treatment with PSI-7977 experienced a virologic breakthrough during the follow-up treatment period with Peg-IFN/RBV. No breakthroughs were observed among patients in the 400-mg arm, although one patient had a viral relapse before SVR at 4 weeks. “This suggests that [the] 400-mg dose achieved a deeper viral suppression,” said Dr. Lawitz.

The extent of viral suppression may be the key difference between the 200- and 400-mg doses of PSI-7977, he said. PSI-7977 at a 400-mg dose may provide a more thorough viral suppression with lower risk for virologic breakthrough. Patients in both groups quickly became negative for HCV RNA after PSI-7977 was started, but patients who received the 200-mg dose had more virologic breakthroughs after the PSI-7977 therapy was completed. No patient in either treatment arm developed an S282T mutation.

Investigators said they were pleased to see that the adverse events reported in the PROTON trial were typical of those seen with Peg-IFN/RBV treatment, except for a small increase in insomnia. Overall, 15% of patients in the 400-mg arm and 8% of those in the Peg-IFN/RBV–only arm reported insomnia.

More cases of neutropenia occurred with PSI-7977 than with Peg-IFN/RBV, but it was unlikely that the difference was significant, said the investigators. Three patients who received PSI-7977 had grade IV neutropenia compared with none in the Peg-IFN/RBV arm. However, the numbers of patients were too low to result in meaningful conclusions.

Still, experts say more patients must be studied to confirm that the new drug is safe.

“The numbers for neutropenia and anemia are confusing to me. They are small numbers but I’m still not certain about the safety of this compound,” said Paul Pockros, MD, head of gastroenterology and hepatology, and director of the Center for Liver Diseases, Scripps Clinic, in La Jolla, Calif.

The study was not powered to detect differences in neutropenia and anemia between the three groups, but differences would be statistically significant if 1,000 patients had participated in the trial, Dr. Pockros explained. “Is this drug going to be safe in 1,000 patients?” he asked.

Dr. Lawitz said investigators would expect to see a difference in adverse events between the 200- and 400-mg arms in this trial if PSI-7977 increased the risk for neutropenia, but that was not the case, with more neutropenia and anemia occurring in the patients receiving the lower dose.

“To me, that suggests that this is a trial with small numbers, and when we get larger numbers the difference is probably not going to be significant,” he said.

PSI 7977, in combination with RBV as dual therapy, is set to enter Phase III trials.

February 2012 - The Hepatitis C Community Advisory Board (HCAB) recognizes the value of more effective and less toxic treatment for hepatitis C virus (HCV). We believe that sponsors can conduct key drug-drug interaction (DDI) studies with direct-acting antivirals (DAAs) and other candidates in development and medications commonly used by people with hepatitis C and those coinfected with HIV/HCV prior to their approval, without delaying development of these important therapies.

DAAs may share metabolic pathways with drugs that are commonly used by populations with a high prevalence of hepatitis C, such as hormonal contraceptives, methadone, buprenorphine, lipid lowering agents, immunosuppressive drugs, herbal remedies, and commonly prescribed psychiatric medications.

In recognition of the suboptimal efficacy and tolerability of peginterferon and ribavirin, rapid trajectory of liver disease progression and increasing mortality from HCV-related complications among HIV/HCV coinfected patients, regulators in the US and the EU encourage sponsors to conduct trials in HIV/HCV coinfected patients prior to approval for HCV monoinfection. Sponsors have already opened, or plan to launch these trials.

The recent discovery of drug-drug interactions between boceprevir and boosted HIV protease inhibitors underscores the importance of DDI studies with DAAs. Although we commend the sponsor, Merck, for opening one of the first coinfection trials with a DAA, we were outraged that Merck chose not to conduct DDIs with commonly used antiretroviral agents prior to launching the trial, and prior to gaining approval for boceprevir. Vertex and Tibotec were able to bring telaprevir to market with a much fuller portfolio of DDI data, although both drugs were developed within the same timeframe.

The FDA Tuesday issued updated safety labeling information for the class of drugs known as statins. The agency noted those drugs’ utility in reducing “bad” cholesterol “when used with diet and exercise” but fine-tuned guidelines for their use.

The new guidelines, aimed at health-care professionals, make it easier for patients to stay on statin therapy by eliminating the need for routine monitoring of liver enzymes. Liver disease among statin users is too uncommon and unpredictable, the agency notes, for such routine screening to be practical. Instead, patients should be screened for liver disease before starting statin therapy and then only if symptoms of liver disease (such as unusual fatigue or weakness, loss of appetite, upper belly pain, dark-colored urine, or yellowing of the skin or the whites of the eyes) appear.

The statement also notes that some patients taking statins may experience memory loss or confusion, but that both those conditions resolve when statin use is discontinued. However, the FDA says, some studies show that statins slightly increase a patient’s risk of elevated blood-sugar levels and of developing type 2 diabetes.

Finally, the statement notes that one variety of statin drugs — lovastatin — may interfere with other medications and lead to muscle damage. Physicians should take care to read the new safety labels for those drugs when prescribing them, the statement says.

Donating part of your liver is just as safe as donating a kidney—donors of these organs have survival rates similar to the rest of the population, according to an article in the February issue of Gastroenterology.

With organ shortages, live-donor liver transplantation (LDLT) is a lifesaving alternative to transplantation from deceased donors for patients with end-stage liver disease. Since the introduction of LDLT 20 years ago, thousands of children requiring liver transplants have benefited from left lateral segment grafts from live donors. Adults now also receive liver transplants from live donors. However, the numbers of livers transplanted from live donors has fallen short of the initial expectations over the past 8 years, due to safety concerns.

To determine the safety and side effects of LDLT, Abimereki Muzaale et al. followed 4111 live liver donors in the US from April 1994 to March 2011. They determined rates of deaths from the Social Security Death Master File and compared survival data with those from live kidney donors and healthy participants of the National Health and Nutrition Examination Survey (NHANES) III.

The authors found that the 90-day mortality of living liver donors (1.7 per 1000 donors or 0.17%) did not differ significantly from that of living kidney donors (0.05%). The long-term cumulative mortality risk was comparable to that of live kidney donors and NHANES participants (1.2%, 1.2%, and 1.4%, respectively) at 11 years.

Kaplan–Meier curves of cumulative mortalities for live donors of livers, matched live donors of kidneys, and matched controls (participants in NHANES III).

There were 4 cases of nonfatal acute liver failure in living liver donors; 3 of these patients required deceased-donor liver transplantation.

In an editorial that accompanies the article, James Trotter and James Everhart state that these results are likely the best estimation of donor mortality, and that this information will be useful for clinicians in counseling potential LDLT donors and recipients. They add that the format of cross-referencing 2 databases provides an important study design for future estimates of donor mortality.

Previous studies reported that physical well-being of donors decreases after surgery, but returns to pre-donation levels within 1 year. Out-of-pocket expenses and lost wages have been estimated to average about $5,000 for donors, although this amount varies greatly.

Nonetheless, Trotter and Everhart say it is important to consider the intangible benefits of an altruistic act. Other benefits include having a loved one remain alive and returned to function, as well as a public health benefit—living donation allows another patient to receive a deceased donor liver, thereby decreasing the demand for deceased donor transplantation.

Trotter and Everhart conclude that the findings of Muzaale et al. set the standard for estimating donor mortality. “Because the liver community has been unable to establish a national database for donor outcomes, and there are no real prospects for such, the rigorous methodology utilized in this study will allow the best means of prospectively reporting living liver donor mortality risk in the future.” However, further studies are needed to determine long-term outcomes of LDLTs.

LOS ANGELES (Reuters) Feb 24 - Gilead Sciences Inc made its name by becoming the leader for drugs against HIV, but a setback for its hepatitis C treatment has opened the door to rivals, making that market tougher to dominate.

Top global drugmakers and tiny biotech companies have over 100 compounds in clinical development to treat the liver-destroying hepatitis C virus (HCV), according to Thomson Reuters Pharma.

The field has attracted broad interest with two new hepatitis C drugs reaching the U.S. market in the past year. Both represent a breakthrough in treatment for a global patient population of up to 170 million.

Gilead and its rivals plan to improve on those medicines with pills that do not need to be combined with injections of immune system boosters such as interferon, which have side effects that can deter patients. They are all vying for a market expected to reach around $10 billion a year, but they may each end up with a smaller slice of the pie.

Gilead spent $11 billion in January to buy Pharmasset and its lead hepatitis C drug candidate in a new class known as nucleotide inhibitors, hoping to be the first to market with an all-oral hepatitis treatment.

But the enthusiasm of investors for the deal was doused last week after Gilead said some patients taking the drug saw the virus return after four weeks. The company's shares are off nearly 20% since the announcement, giving back some of the 50% gain in the wake of the Pharmasset purchase.

Gilead's stumble may make way for rivals such as Bristol-Myers Squibb Co, which recently bought Inhibitex for $2.5 billion, or a premium of 163%, to boost its HCV portfolio. It has already fueled additional interest in much smaller competitors Achillion Pharmaceuticals Inc and Idenix Pharmaceuticals Inc.

GOAL IS ALL-ORAL TREATMENT

Traditional hepatitis C therapy requires a year of treatment with a combination of interferon and ribavirin. It can cure about half of treated patients, but harsh flu-like side effects prevent many from reaching that goal.

Greater knowledge of genetics and molecular function has led to several new classes of direct acting antiviral drugs, which are expected to revolutionize treatment.

"The goal is to go interferon-free over the next few years, and have an all-oral regimen that basically can eradicate the virus in over 80% of people who are infected in 12 to 24 weeks," said Dr. Fred Poordad, chief of hepatology and liver transplantation at Cedars-Sinai Medical Center in Los Angeles.

Dr. Poordad is involved in "about 90%" of current hepatitis C trials and sees several viable treatment regimens becoming available.

"This is not going to be a winner takes all type of thing," he said.

Around 3.2 million Americans -- mainly baby boomers -- have chronic hepatitis C, according to the U.S. Centers for Disease Control and Prevention. The rate of new U.S. infections has slowed to around 17,000 a year following the introduction of blood and organ donor screening in the early 1990s and greater awareness of the risk from shared needles.

The virus is often undiagnosed and contracted through contact with blood from an infected person. There may be few initial symptoms, but it is the leading cause of liver transplants and can cause liver cancer.

Hepatitis C killed more than 15,000 Americans in 2007, compared with a little over 12,700 deaths related to HIV, according to recent CDC statistics.

New drugs include protease inhibitors, which aim to block enzymes used by the viruses to cling to certain proteins; nucleotide or nucleoside inhibitors, also known as "nukes," which interfere with enzymes needed for viral replication; and blockers of NS5A, a protein essential to viral replication.

Two new protease inhibitors launched last year -- Incivek from Vertex Pharmaceuticals Inc and Merck & Co's Victrelis -- are still taken with interferon and ribavirin.

Gilead's GS-7977, a nucleotide inhibitor, was supposed to work without interferon. But the latest data on patients who have not responded to earlier treatment showed the drug may need to be combined with additional antiviral medications.

Bristol-Myers acquired an experimental nucleotide inhibitor through the Inhibitex deal and it also has a promising NS5A inhibitor. The shares of Idenix, which has nucleotide inhibitors in development, have soared 64% so far this year.

Novartis AG said this week it would pay $34 million upfront and $406 million in milestone payments to license an NS5A inhibitor from Enanta Pharmaceuticals.

Other companies with second generation protease inhibitors include Johnson & Johnson and Merck. Roche Holding AG and Vertex are developing nukes and other all-oral hepatitis C drug regimens are being explored by Abbott Laboratories, Pfizer Inc and Boehringer Ingelheim.

Investor enthusiasm runs high, and on very early evidence. The shares of another small company, Biocryst Pharmaceuticals Inc, shot up 12% in a single day after it said experimental hepatitis C drug BCX5191 showed promise in rat testing.

NO WINNER TAKES ALL

Julie Hoggatt, an analyst with Wolters Kluwer's inThought, puts the total market for hepatitis C drugs in the United States, Europe and Japan at $10.4 billion in 2016, falling to $8.6 billion in 2021 as more patients are cured and new infection rates decline.

Hoggatt estimated that only about 60,000 U.S. hepatitis C patients are currently being treated.

"Over the next 10 years, we are going to treat the majority of (U.S.) patients," she said.

Current treatments run about $60,000 a year and analysts estimate the eventual cost of a course of therapy at between $40,000 and $100,000.

"It will be a fragmented market and everybody is going to be fighting over the $500- to $800-million-a-year range," she said. "It is hard for one player to get into billions a year."

Others are much more bullish. Pharmasset, in its regulatory filings, forecast that its own worldwide sales of HCV drugs would peak at $8.2 billion in 2017, falling to a run rate of $4.5 billion in 2025.

Its new owner Gilead has been more circumspect and forecasts a longer time frame to bring patients on board.

"We think there's a lot of patients that can be captured both in the United States, Europe, and other territories, which could provide for a very long and sustained revenue and cash flow stream for Gilead," Chief Operating Officer John Milligan said earlier this month.

GS-7977 Plus Ribavirin Will Displace the Current Proprietary Clinical Gold Standard, Telaprevir in Combination with Peg-IFNa/Ribavirin, According to Findings from Decision Resources

BURLINGTON, Mass., Feb 28, 2012 (BUSINESS WIRE) -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that, based on clinical data and the opinions of interviewed thought leaders, telaprevir (Vertex's Incivek, Johnson & Johnson's Incivo) in combination with peg-IFNa (Roche's Pegasys or Merck's Victrelis) and ribavirin (Roche's Copegus; Merck's Rebetol; generics) has earned Decision Resources' proprietary clinical gold standard status for the treatment of non-responder patients with hepatitis C virus (HCV). Owing to its competitive advantages in safety and tolerability as well as delivery, the interferon-free combination of Gilead's GS-7977 (formerly PSI-7977) plus ribavirin will displace telaprevir plus peg-IFNa/ribavirin and earn proprietary clinical gold standard status for HCV non-responders in 2015, following its launch for the indication in 2014 in the United States.

Decision Resources' analysis of the hepatitis C virus drug market also finds that surveyed U.S. gastroenterologists and managed care organization (MCO) pharmacy directors agree that the percentage of genotype-1 null responders achieving sustained virologic response is one of the attributes that most influences their decisions regarding prescribing and formulary status determinations, respectively, in HCV non-responders.

According to insights from surveyed U.S. gastroenterologists and MCO pharmacy directors, the absence of interferon-free treatment options for HCV is one of the greatest unmet needs in HCV. Clinical data and the opinions of interviewed thought leaders indicate that GS-7977 has demonstrated the potential to significantly fulfill this unmet need.

The findings also reveal that surveyed U.S. gastroenterologists indicate that they would prescribe the quadruple regimen of Bristol-Myers Squibb's NS5A inhibitor daclatasvir (BMS-790052) plus Bristol-Myers Squibb's protease inhibitor asunaprevir (BMS-650032) plus peg-IFNa/ribavirin to 41 percent of their HCV non-responder patients. Decision Resources' forecast for this quadruple regimen is more conservative due to anticipated reimbursement restrictions, positioning in later lines of therapy, competition from IFN-free regimens and competition asunaprevir will face from other protease inhibitors.

The launch of novel HCV-specific agents will increase the size of the drug-treated population mainly as a result of re-treatment of prior non-responders as well as increased referral and drug treatment rates. The overall HCV drug market will experience significant growth, expanding from almost $1.7 billion in 2010 to $14.4 billion in 2015 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan. Thereafter, the market will decrease to $11.2 billion in 2020, owing to a decline in the size of the treatment-eligible population due to declining prevalence and effective new regimens.

Decision Resources' Robust Market Forecast and Opportunities Analysis

Decision Resources provides a comprehensive view of what is happening in a specific drug market now and in the decade ahead. The research includes analysis of the unmet need and near-term drug development opportunities that exist within a drug market powered by primary research from physicians and payers. The robust market forecast and opportunities analysis is comprised of the Pharmacor 2012 advisory service and the DecisionBase 2012 report series.

About Decision Resources

Decision Resources ( www.decisionresources.com ) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources Group company.

About Decision Resources Group

Decision Resources Group is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources Group at www.DecisionResourcesGroup.com .

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SALT LAKE CITY, Feb. 27, 2012 – University of Utah mathematicians developed a set of calculus equations to make it easier for doctors to save Tylenol overdose patients by quickly estimating how much painkiller they took, when they consumed it and whether they will require a liver transplant to survive.

"It's an opportunity to use mathematical methods to improve medical practice and save lives," says Fred Adler, a professor of mathematics and biology and coauthor of a study that developed and tested the new method.

The study of acetaminophen – the generic pain and fever medicine sold as Tylenol and in many other nonprescription and prescription drugs – was set for publication within a week in Hepatology, a journal about liver function and disease.

Adler, math doctoral student Chris Remien and their colleagues showed that using only four common medical lab tests – known as AST, ALT, INR and creatinine – the equations can quickly and accurately predict which Tylenol overdose patients will survive with medical treatment and which will die unless they receive a liver transplant.

The researchers analyzed the records of 53 acetaminophen overdose patients treated at the University of Utah's University Hospital to test the equations and show they quickly and accurately predicted, in retrospect, which patients survived and which died.

Speed is essential in listing acute liver failure patients as candidates for transplant, says study coauthor Norman Sussman, a former University of Utah liver doctor now at the Baylor College of Medicine in Houston.

If a doctor is uncertain and starts to treat an acetaminophen-poisoning patient with the antidote to combat liver failure – even though the patient may not survive with such medicine – their odds for getting a new liver are reduced.

"If I wait another day until I list them for transplant, the chance of getting a liver is that much lower," Sussman says. "If you're going to get someone transplanted, you have to do it fast or you miss the boat. The patient may pass the window when transplants can be done. They become too sick and can't stand the transplant."

The new method using calculus equations will let doctors rapidly determine if a patient can survive with antidote treatment or will die unless they get a transplant.

The study urges another clinical trial to prove the new method's usefulness. Sussman plans to start a one-year prospective trial testing the method on 50 patients at the University of Utah and three hospitals in Houston.

If that trial proves the method can accurately predict ahead of time how Tylenol-poisoning patients will fare, "we believe we could create a tool available and immediately useful to clinicians," Sussman says. Adler foresees a smartphone application.

Adler, Remien and Sussman conducted the study with University of Utah hepatologist Terry Box and Lindsey Waddoups, clinical research coordinator for the University of Utah's gastroenterology division. The research was funded by a National Science Foundation grant to the University of Utah's program in mathematical biology.

Painkiller Can Be a Killer

Acetaminophen – the primary generic name for the drug also known generically as APAP and paracetemol – is found in prescription medicines such as Tylenol with Codeine, Percocet or Vicodin, and in dozens of over-the-counter medications, including Tylenol, Anacin, Pediacare, Triaminic and combination cold medications like Nyquil.

Many people don't realize the common analgesic can destroy the liver and kill at only about five times the recommended dosage – a narrow margin in medical terms.

"Acetaminophen is the leading cause of acute liver injury in the United States, accounting for some 56,000 emergency room visits, 26,000 hospital admissions and about 500 deaths annually," Adler and his coauthors write.

University of Utah mathematicians Chris Remien and Fred Adler with some of the calculus equations that are part of a new method they developed and tested to make it easier for doctors to save Tylenol overdose patients by quickly determining if they can be saved with an antidote or will require a liver transplant to survive.

(Photo Credit: Lee J. Siegel)

The current maximum dose of acetaminophen is 4 grams (4,000 milligrams or eight 500 milligram tablets, for example) in 24 hours. There is not a lot of room for error between that 4-gram maximum and the 6 grams that can cause liver damage or the 20 grams that are considered likely to destroy 70 percent of liver cells and cause death.

Acetaminophen overdoses can be treated successfully if an antidote named N-acetylcysteine (N-Ac or "nack") is administered within roughly 24 hours. After a certain time post-overdose, treatment becomes futile and the patient will die without a transplant.

Yet many overdose patients are confused or comatose, unable to say how much acetaminophen they took or when they took it, making it tough to predict their prognosis.

Life-Saving Calculus

The new method uses eight main "differential equations" – basic calculus equations that describe how changes in one variable affects changes in another variable over time. The equations simulate or "model," step-by-step, how acetaminophen is metabolized in the liver, including production of NAPQI, a liver-destroying substance.

That makes it the first known "dynamical" model based on real biology – a contrast to the existing "statistical" method for determining how overdose patients fare.

The statistical method – known as the King's College Criteria (KCC) – estimates who is likely to survive or die from acetaminophen toxicity using correlations between INR and creatinine lab tests and which patients actually did live or die in the past. The King's College Criteria predict liver failure if INR exceeds 6.4, creatinine exceeds 3.4 and there is confusion, altered consciousness or coma due to liver damage.

The problem, says Adler, is the criteria "look at the statistical relationship between lab test results and patient outcome without understanding what's happening inside the liver. It's just statistics."

The new method "tracks how the liver's health changes over time," he says.

The new equations use patients' measured levels of AST, ALT and INR to estimate when they consumed acetaminophen and how much they took. By also considering creatinine levels, the new method accurately predicts which Tylenol overdose patients will survive with treatment and which will require a liver transplant to avoid death.

AST (aspartate aminotransferase) and ALT (alanine aminotransferase) are enzymes that are released by dying liver cells, so higher levels indicate liver damage. INR (prothrombin time/international normalized ratio) measures how fast blood clots. Liver cells make clotting factors, so if the liver malfunctions, clotting is slower. Creatinine is a measure of kidney dysfunction, in this case secondary to liver damage.

Sussman says the King's College Criteria are outdated and have grown less useful over time. When a patient arrives with lab results indicating liver failure, "your first decision has to be, 'Do I list this patient for transplant?'" he says. "That was the purpose of the King's College Criteria. You need to make an immediate decision: Do I think this patient will live or die? If I think they'll live, I'm going to treat them [with the antidote]. If they're going to die, the next question is, are they a candidate for transplant?"

"Our goal was to try to trace it back to: when did the damage start?," he adds. "Once you know that and the peak damage reflected in the ALT, then you have the tools to predict survival or death."

Of people who are liver transplant candidates, those with acute liver failure – half due to acetaminophen poisoning – go straight to the top of the liver transplant list, ahead of the vast majority of candidates who have chronic liver failure, such as from alcoholism, Sussman says.

Predicting Overdose Outcomes

The 53 patients whose records were analyzed for the new study varied in alcohol use, malnutrition status and whether they took too much acetaminophen in a suicide attempt, an accidental single overdose or a chronic, multiple-day overdose.

Two patients got liver transplants and were excluded from the analysis "because we don't know if they would have died or recovered without transplant," Remien says.

Of the 51 remaining patients, eight died and 43 survived. The study showed that when AST, ALT and INR tests on admission were crunched through the equations, and when creatinine levels exceeded 3.4, the method was highly accurate in predicting, retrospectively, whether overdose patients lived or died. Specifically, the method had:

100 percent sensitivity, meaning the method correctly predicted the deaths of all eight patients who actually had died. By comparison, the King's College Criteria predicted only one of the eight deaths.

Sussman says there were multiple reasons for the eight deaths. Some patients arrived too late to be treated, even by a transplant, and others didn't qualify as transplant candidates, perhaps due to serious drug or alcohol abuse and lack of family support.

About 16,000 people now are on the liver transplant waiting list in the United States. About 5,000 to 6,600 Americans get liver transplants each year.

Adler emphasizes the new method is based on a typical acute liver failure patient and may need refinement to better predict the prognoses of certain special patients, including those taking other drugs, with chronic alcohol use or suffering anorexia.

Cambodia's health officials said Sunday that a study found that at least seven species of freshwater fishes in the country can cause human liver cancer when they have not been cooked well before eating.

Dr. Char Meng Chuor, director of the National Center for Parasitology, Entomology and Malaria Control, said that the recent study was conducted by two Japanese scientists from Dokkyo University in cooperation with the center.

The seven species of the freshwater fishes are scientifically named Cyclocheilichthys apogon, a type of beardless barb; Cyclochelichthys enoplos, a ray-finned fish in the genus Cyclocheilichthys; Cyclocheilichthys repasson, a species of ray- finned fish in the genus Cyclocheilichthys; Puntius brevis, a species of ray-finned fish in the genus Puntius; Hampala dispar, a type of spotted Hampala barb, Barbonymus altus, a red-tail tinfoil barb; and Cirrhinus lobatus in a species of ray-finned fish. "Human liver fluke, a freshwater parasite endemic, is detected in these fishes and those parasitic flatworms can trigger human liver cancer by creating harmful cell mutations, causing tumor growth and stopping normal cell death," he said. "When a person eats the fish raw, or some Cambodians eat a delicacy of fermented fish, the parasitic flatworms will take up residence inside the liver,"he said. "However, we can prevent the disease easily by eating only well-cooked fish."

Muth Sinuon, head of the National Program for Helminthiasis ( macro parasitic disease of humans and animals) at National Center for Parasitology, Entomology and Malaria Control said that the liver cancer that is caused by eating those raw fish has not only happened in Cambodia, but also in Laos, Vietnam, the Philippines, Indonesia, especially Thailand, because Thai people are keen to eat uncooked fish.

Johann Wolfgang Goethe University Hospital Becomes Second Training Center in Europe to Treat Patients with Delcath Hepatic CHEMOSAT® Delivery System

NEW YORK, Feb. 27, 2012 /PRNewswire via COMTEX/ -- Delcath Systems, Inc. announced today that the first patients in Germany have been treated with the Delcath Hepatic CHEMOSAT® Delivery System at the Johann Wolfgang Goethe University Hospital, a premier European cancer treatment and research center located in Frankfurt. The cases were treated as part of the initial launch and training agreement the Company announced with the hospital in December 2011.

Two patients were treated for inoperable, liver-dominant metastases, one from cutaneous melanoma and one from breast cancer. The treating physicians reported that both patients were treated successfully without procedure-related complications.

Dr. Thomas J. Vogl, Director of the Institute for Diagnostic and Interventional Radiology at J.W. Goethe, said, "We believe this technology has significant potential to help control cancers in the liver. We're pleased to be the first cancer center to begin offering this important treatment option to patients in Germany, and are eager to further explore its role in the treatment of multiple tumor types including breast cancer."

"Delcath's partnership with J.W. Goethe reinforces the potential of CHEMOSAT," said Eamonn P. Hobbs, president and CEO of Delcath. "We recently treated our first patients in Milan and are eager to continue our expansion across Europe. Opening another CHEMOSAT treatment center and treating patients in the continent's largest market is another step forward in the commercialization of this technology."

About the Johann Wolfgang Goethe University Hospital

Founded in 1914, J.W. Goethe University Hospital is considered to be one of the leading university hospitals in Germany. Twenty-five research institutes working in close cooperation with the Medical Department bear witness to the hospital's strong academic approach. This makes sure that patients coming to the University Hospital for treatment enjoy the benefits resulting from timely implementation of research findings. Every year, around 47,200 and 220,000 patients respectively receive in- and outpatient treatment. The University Hospital possesses special interdisciplinary competence in the fields of neurological science, oncology and cardiovascular medicine.

About Delcath Systems

Delcath Systems, Inc. is a development stage specialty pharmaceutical and medical device company focused on oncology. Delcath's proprietary system for chemosaturation is designed to administer high dose chemotherapy and other therapeutic agents to diseased organs or regions of the body, while controlling the systemic exposure of those agents. The Company's initial focus is on the treatment of primary and metastatic liver cancers. In 2010, Delcath announced that its randomized Phase III clinical trial for patients with metastatic melanoma in the liver had successfully achieved the study's primary endpoint of extended hepatic progression-free survival. The Company also completed a multi-arm Phase II trial to treat other liver cancers. The Company obtained authorization to affix a CE Mark for the Hepatic CHEMOSAT delivery system in April 2011. The right to affix the CE mark allows the Company to market and sell the CHEMOSAT system in Europe. The Company has not yet received FDA approval for commercial sale of its system in the United States. The Company continues with the preparation of its NDA submission and intends to seek FDA approval for commercial sale of its chemosaturation system with melphalan. For more information, please visit the Company's website at www.delcath.com

The Private Securities Litigation Reform Act of 1995 provides a safe harbor for forward-looking statements made by the Company or on its behalf. This news release contains forward-looking statements, which are subject to certain risks and uncertainties that can cause actual results to differ materially from those described. Factors that may cause such differences include, but are not limited to, uncertainties relating to: the future use and adoption of the CHEMOSAT system by the J.W. Goethe University Hospital, patient outcome resulting from treatment with the CHEMOSAT system, future initial launch and training agreements with other cancer centers in Europe, CE Marking for the Generation Two system and the timing of our commercial launch in Europe, the time required to build inventory and establish commercial operations in Europe, adoption, use and resulting sales, if any, for the Hepatic CHEMOSAT delivery system in the EEA, our ability to successfully commercialize the chemosaturation system and the potential of the chemosaturation system as a treatment for patients with terminal metastatic disease in the liver, acceptability of the Phase III clinical trial data by the FDA, our ability to address the issues raised in the Refusal to File letter received from the FDA and the timing of our re-submission of our NDA, re-submission and acceptance of the Company's NDA by the FDA, approval of the Company's NDA for the treatment of metastatic melanoma to the liver, adoption, use and resulting sales, if any, in the United States, approval of the current or future chemosaturation system for other indications, actions by the FDA or other foreign regulatory agencies, our ability to obtain reimbursement for the CHEMOSAT system, our ability to successfully enter into distribution and strategic partnership agreements in foreign markets and the corresponding revenue associated with such foreign markets, uncertainties relating to the results of research and development projects and future clinical trials, and uncertainties regarding our ability to obtain financial and other resources for any research, development and commercialization activities. These factors, and others, are discussed from time to time in our filings with the Securities and Exchange Commission. You should not place undue reliance on these forward-looking statements, which speak only as of the date they are made. We undertake no obligation to publicly update or revise these forward-looking statements to reflect events or circumstances after the date they are made. Investor Contact: Doug Sherk/Gregory Gin EVC Group 415-568-4887/646-445-4801

Japanese scientists have recently discovered that hydrogen sulfide (H2S) – the chemical responsible for such malodorous phenomena as human flatulence, bad breath and rotten eggs – can be used to efficiently convert stem cells from human teeth into liver cells.

While the fetid chemical compound is produced in small quantities by the human body for use in a variety of biological signaling mechanisms, at high concentrations it is highly poisonous and extremely flammable.

A team of researchers at the Nippon Dental University in Tokyo collected stem cells from the teeth of patients undergoing extractions. The cells were harvested from the central part of the tooth known as the pulp which is made up predominantly of connective tissue and cells.

Stem cells recovered from the pulp were then divided into two groups and incubated in sealed chambers, one filled with hydrogen sulfide and the other a control group.

The cells from each chamber were then examined at three-day intervals to look for signs of transformation into liver cells. One such indicator is the ability to store glycogen, a compound that can be converted to glucose when the body needs energy.

According to a report of their findings that appeared this week in the Journal of Breath Research, the team was able to convert the stem cells to liver cells in relatively high numbers. And what’s more, said the team, H2S appears to help produce comparatively high quality, functional liver cells.

Lead researcher Ken Yaegaki explained that “[h]igh purity means there are less ‘wrong cells’ that are being differentiated to other tissues, or remaining as stem cells … These facts suggest that patients undergoing transplantation with the hepatic cells may have almost no possibility of developing teratomas (malignant tumors) or cancers.”

For the thousands of people around the world with chronic liver disease, this is a most welcome discovery, one that Yaegaki believes could potentially revolutionize this field of medicine.

“Until now, nobody has produced the protocol to regenerate such a huge number of hepatic cells for human transplantation,” added Yaegaki.

“Compared to the traditional method or suing fetal bovine serum to produce the cells, our method is productive and, most importantly, safe.”

Yaegaki’s hope is that his team’s discovery may eventually be fine-tuned to allow scientists to produce ample liver cells in a lab for use in repairing liver damage in human patients.

Moreover, this and similar studies in recent years have also gotten researchers in other fields questioning the possibilities for using hydrogen sulfide with other types of stem cells.

A team of researchers in China, for instance, recently reported using H2S to increase the survival rate of mesenchymal stem cells extracted from the bone marrow of rats.

Using a computer model of the hepatitis C disease, Stanford researchers have shown that two new drugs intended to target the virus are cost-effective for patients suffering from advanced hepatitis C, despite some significant side effects.

Hepatitis C, a virus that leads to swelling or inflammation of the liver, is now killing more Americans than the HIV virus. The majority of the 3.2 million people estimated to have chronic hepatitis C in the United States are baby-boomer adults, according to a Scientific American blog.

Jeremy Goldhaber-Fiebert, an assistant professor of medicine, and his research team examined treatments that involved pegylated interferon alongside ribavirin — collectively deemed the standard two-drug therapy — and compared it to a “triple therapy,” with either boceprevir (trade name Victrelis) or telaprevir (trade name Incivek) added to the standard two-drug therapy.

Both drugs entered the commercial market in the summer of 2011, and — though they decrease the chance of chronic hepatitis C — both have severe side effects.

The most common adverse drug reactions to Incivek, as listed by the Food and Drug Administration (FDA), include rash, pruritus, anemia, nausea, hemorrhoids and diarrhea. Victrelis is associated with an additional decrease in hemoglobin concentrations, resulting in fatigue, anemia, nausea, headache and dysgeusia.

The research team, which included graduate students Shan Liu and Lauren Cipriano M.S. ‘11 as well as Professors of Medicine Mark Holodniy and Douglas K. Owens, designed a model to comparatively examine the advantages and disadvantages of three treatment strategies: giving all hepatitis C patients the standard treatment, giving all of them a triple therapy and giving triple therapy only to the patients less likely to respond to standard treatments.

“The computer model we developed includes the health risks, quality of life changes and costs for patients who have genotype 1 chronic hepatitis C infection as well as the effectiveness, costs, side effects [and] quality-of-life changes of undergoing various treatments for chronic hepatitis C,” Goldhaber-Fiebert said. “An expensive treatment, even with some side effects, may be beneficial overall if it is more effective, thereby prolonging life, improving quality and/or averting costs compared to not undergoing treatment.”

Statistical and simulation analysis showed that the new triple therapies were cost-effective for chronic hepatitis C patients with advanced liver disease. For patients with a mild case of the disease, the model’s findings advised determining their IL-28B genotype — associated with gauging whether the standard two-drug treatment will be effective — before deciding on treatment.

“Protease inhibitors increase the effectiveness of standard therapy, but they are costly,” the team’s study states. “A genetic assay may identify patients most likely to benefit from this treatment advance.”

The study links how imminent the threat of severe disease is with justifying the costs and risks of the “triple therapy.”

Despite the costs, universal triple therapy reduced the lifetime risk for liver carcinoma by 38 percent in cases of mild fibrosis and 28 percent in incidents of advanced fibrosis, increasing the quality-adjusted life expectancy by three percent and eight percent, respectively, compared with standard therapy, the study showed.

The study concluded that, “universal triple therapy and IL-28B guided triple therapy are cost-effective when the least-expensive protease inhibitor is used for patients with advanced fibrosis.”

High Wycombe, UK, 27th February 2012: Janssen has today launched a new partnership with Bupa Home Healthcare which will support chronic genotype-1 hep C patients undergoing an INCIVO®(telaprevir) based treatment regimen (telaprevir in combination with peginterferon alfa and ribavirin).

Speaking at the launch of the MYINCIVO™ Support Programme, Dr Peter Barnes, Medical Director at Janssen stated: “We recognise that treatment for hep C can be challenging and demands significant commitment from patients. We also recognise that the addition of telaprevir, one of a new class of medicines which directly targets the hep C virus, to the current standard treatment adds another element of complexity. That is why today we are launching this programme to support patients 24 hours a day, 7 days a week for the full duration of their treatment if they are initiated on a telaprevir based treatment regimen.”

Before the introduction of protease inhibitors, of which telaprevir is the latest, treatment for genotype-1 chronic hep C cleared the virus in only about 50% of patients, leaving the other 50% without a successful outcome following 12 months of treatment1. Clinical trials have shown that a telaprevir based regimen is more effective than standard treatment in all genotype-1 patient types, including those with compensated liver disease such as cirrhosis. The addition of telaprevir to the current standard treatment (i.e. peginterferon alfa and ribavirin) cleared the virus in a significantly greater number of those patients who had previously been untreated (79% vs 46%, p<0.0001). In patients who had relapsed after previous treatment nearly four times as many cleared the virus in the telaprevir arm (84% vs 22%, p<0.0001)2,3,4. In addition, treatment naive patients and prior treatment relapsers who achieve undetectable levels of hep C virus RNA on testing at weeks 4 and 12 can have their total treatment duration reduced to 24 weeks from the current 48 weeks with standard treatment5. A key factor in achieving these results was good adherence to treatment5.

In developing the MYINCIVO™ Support Programme Janssen worked with Bupa Home Healthcare, healthcare professionals and patient support groups to ensure patients have access to confidential advice and support to help them adhere to their medication, to take care of themselves, stay motivated and in control while going through treatment. Most importantly, the MYINCIVO™ Support Programme is intended to complement the care being provided by a patient’s hep C specialist healthcare professional and helps with continuity of the patient’s care and support. The MYINCIVO™ Support Programme can also be accessed by patients’ partners, carers or family members as appropriate.

Dr Mehmood Syed, Medical Director at Bupa Home Healthcare stated: “Providing tailored support to get better health outcomes for the individual is at the heart of this programme. We want to empower patients so that they have more control over their health as well as provide them with dedicated medical expertise and support when they need it”.

The programme is personalised to the needs of the individual patient via the MYINCIVO™ case management platform and the MYINCIVO™ dedicated nurse team are experienced in, and trained to provide additional advice and support on many issues. The MYINCIVO™ support programme is completely confidential between the patient, their hep C specialist healthcare professional and BUPA. It includes support such as a SMS text dose reminder service (to promote adherence), health coaching (to motivate, promote adherence, health & wellbeing), advice and information including healthy living, foods to eat while on treatment and dealing with symptoms and side-effects specific to patients who have been prescribed a telaprevir-based regimen.

The overall safety and tolerability profile of telaprevir is based on the phase II and III clinical development programme. The most frequently reported moderate adverse reactions (incidence = 5.0%) were anaemia, rash, pruritus, nausea, and diarrhoea, and the most frequently reported severe adverse reactions (incidence = 1.0%) were anaemia, rash, thrombocytopenia, lymphopenia, pruritus, and nausea5.

Rash events were reported in 55% of patients with telaprevir based treatment compared with 33% in the control arm (peginterferon alfa and ribavirin only). More than 90% of rashes were of mild or moderate severity. Severe rashes were reported with telaprevir based treatment in 4.8% of patients. Rash led to discontinuation in 5.8% of patients. Anaemia was reported in 32.1% of patients compared with 15% in the control arm (peginterferon alfa and ribavirin only). It led to discontinuation in approximately 3% of patients5.

In the UK, it is estimated that 216,000 to 466,000 individuals are chronically infected with hepatitis C, a virus that is carried in blood and predominantly affects the liver, of which only 80,000 have been diagnosed6,7. Chronic hep C poses a public health burden. It is an infectious disease, with often no symptoms, that can lead to severe liver conditions. Of those who develop chronic hepatitis C an estimated 30% will develop cirrhosis (deterioration of the liver), others will develop liver cancer, some of whom may require liver transplantation1. Chronic hep C is the most common reason for liver transplants in Europe8.

* INCIVO® (telaprevir), a direct acting antiviral (DAA) protease inhibitor (PI), was co-developed by Vertex Pharmaceuticals and Tibotec, an affiliate of Janssen Pharmaceutical Companies of Johnson & Johnson, and the company responsible for marketing telaprevir in Europe.

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